Lenvatinib Plus Belzutifan Shows Promise for Advanced Clear Cell Renal Cell Carcinoma

Katy Beckermann, MD, Vanderbilt University, Nashville, Tennessee, discusses results from the KEYMAKER-U03 Substudy 03B, evaluating pembrolizumab in combination with targeted therapy agents for patients with advanced clear cell renal cell carcinoma. According to these data, lenvatinib plus belzutifan showed durable antitumor activity with an expected safety profile and should be further investigated.

These data were first presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Transcript:

Hi everyone. It's a pleasure to be here. My name is Katy Beckermann. I'm a GU medical oncologist. I'm currently the medical director for GU Research at Tennessee Oncology. And it was my pleasure to present at GU ASCO 2025 work that I conducted while an assistant professor at Vanderbilt University on a clinical trial called KEYMAKER-U03-03B. It was a clinical trial testing novel combination therapies. And I specifically was fortunate to be part of this trial and present the targeted therapy combination arms at this conference. And it was testing these targeted therapy combination arms in patients who have refractory clear cell carcinoma. 

To take a step back, I think we all recognize that frontline treatments and combinations with PD-1 regimens as the backbone have certainly made huge advances for patients over the last 5 to 8 years. But it's still the case that most patients ultimately, unfortunately go on to progress on that frontline treatment regimen. The current standard of care in the second and sequential lines is sequencing of targeted therapies, such as tyrosine kinase inhibitors or TIF inhibition. So the hypothesis for the conducting of this trial was could we combine novel targets to help benefit our patients? 

And to give you a sense of the patients that were able to enter into this trial, the inclusion criteria required clear cell histology and required patients to have progressed on at least both 1 prior PD-1 and a VEGF tyrosine kinase inhibitor. And then it was a phase 1/2; it was an open label, rolling arm, umbrella platform. So it was multiple different arms and there was always a safety lead in for the investigational arm, followed by that expansion cohort. So looking at the baseline characteristics of these patients, it really was a very refractory patient population. About a third of patients had had 2 or [more] lines of therapy, and almost 50% on each arm had had 3 or more lines of prior therapy before entering this study. About two thirds of patients having intermediate risk IMDC criteria. 

And the arms that I presented were a combination of pembrolizumab and belzutifan, a combination of belzutifan with lenvatinib, and then I also presented data from a lenvatinib plus pembrolizumab reference arm. Statistically these arms, the primary endpoint was ORR [objective response rate], and these arms were not compared amongst each other, and so it was the efficacy estimated per individual arm. Having said that, there was approximately 60 patients in each arm with a median follow-up of about 17 months, so shorter term follow-up on these trials. But looking across these different arms in the refractory setting, we saw an ORR in the pembrolizumab plus belzutifan arm of 17%. We saw an objective response rate in the lenvatinib plus belzutifan arm of 47%. And in the reference arm of pembrolizumab and lenvatinib, we saw an objective response rate of 40%. 

If we then look at some of the secondary endpoints: progression-free survival and overall survival data was presented. The median PFS on the lenvatinib plus belzutifan arm was 12.5 months. The median PFS on the lenvatinib plus pembrolizumab arm was about 9 months. And again, a median PFS on the pembrolizumab plus belzutifan arm of approximately 5 months. And then again, short-term follow-up but the OS survival rates were 67% at 12 months of patients were alive in the pembrolizumab and belzutifan arm. And the other 2 arms, the lenvatinib plus belzutifan as well as the pembrolizumab plus lenvatinib arm both had a 12-month overall survival rate of about 88%. 

We also, of course, trying to dose intensify in a refractory patient population, wanted to be very mindful about the AE [adverse event] profile, looking across these various treatment arms. And the expected safety was determined by each of the targeted treatment options. Where we saw tyrosine kinase inhibitors, we saw the expected hypertension, proteinuria, hand-foot syndrome, and there did not seem to be an increase in the percentage of AEs when these novel combinations were tried together. There were similar rates of discontinuation, approximately 10% of patients in each arm required discontinuation of study drug for AE. 

Overall, to put all this data into context, the pembrolizumab plus belzutifan arm in a refractory patient population had a similar objective response rate and a similar median PFS that we saw in LITESPARK-005 with that belzutifan monotherapy arm, suggesting, again, that maybe pembrolizumab in a patient who's already progressed on checkpoint inhibition is not adding much, similar to what we saw at TiNivo2 and CONTACT-03. In the pembrolizumab and lenvatinib arm that gave us additional data to understand how lenvatinib might be performing in a refractory patient population there with an ORR of 40%, which is again in a very heavily pretreated patient population. 

And then lastly, the combination of lenvatinib plus belzutifan showed an ORR of 47% and a median PFS of 12 months. This combination is being studied right now in a larger randomized phase 3 that was actually already ongoing before this arm read out. And so that is LITESPARK-011 and I think will help give us further data to understand if that's going to be a beneficial regimen for patients who have refractory clear cell carcinoma. Thank you all so much for your attention. 

Source:

Albiges K, Suárez C, Powles T, et al. KEYMAKER-U03 Substudy 03B: Pembrolizumab (pembro) and targeted therapy combinations for advanced clear cell renal cell carcinoma. Presented by 2025 ASCO Genitourinary Cancers Symposium. February 13-15, 2025; San Francisco, CA. Abstract 440.